Neurotensin (NT), a neuropeptide that does not have affinity for dopamine or serotonin receptors, has been shown to produce antipsychotic drug (APD)-like preclinical effects when administered directly into the brain. These findings have raised the possibility that NT agonists may be developed as novel APDs. Recently, NT agonists that access the brain after systemic administration have become available and they are excellent tools to study the APD potential of NT. Preliminary studies conducted in the PI's laboratory testing these NT agonists in animal models of deficient prepulse inhibition (PPI) of the startle response, support the contention that they have APD-like potential. One aim of this application is to investigate the APD profile of NT agonists. Using prototypical APDs of the typical and atypical families as comparators, the proposed studies will test the NT agonist PD149163 in complementary behavioral and molecular animal models that are highly predictive of the clinical efficacy of APDs. These studies will specifically investigate whether systemically administered PD149163 is likely to have a therapeutic effect on positive psychotic symptoms and negative symptoms, and whether it is likely to induce extrapyramidal side effects. Whether PD149163's APD-like effects are mediated by NT receptors will also be investigated by using selective NT antagonists. Established APDs stimulate synthesis and release of endogenous NT in the brain, and preliminary studies suggest that endogenous NT may mediate the effects of APDs. Therefore, a second aim of this proposal is to test the contention that endogenous NT contributes to the therapeutic effects of established APDs. Experiments will investigate the ability of NT antagonists to inhibit the effects of typical and atypical APDs in two nonpharmacological animal models of PPI that are predictive of clinical APD efficacy. Results of the proposed studies are predicted to support the contention that endogenous NT mediates the effects of APDs by activating NTR1 receptors and that exogenous NT agonists, like PD149163, produce atypical APD-like effects by activating the same receptors. These findings would support the development of NT-based, novel APDs and also drive future studies aimed at elucidating the circuitry for NT-mediated APD effects as a means of understanding the mechanisms underlying the therapeutic effects of APDs that occur beyond the well-established receptor actions they produce.